Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:10][CH3:11])=[N:4][CH:5]=[N:6][C:7]=1[O:8][CH3:9].[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C.C1COCC1>[CH3:11][O:10][C:3]1[C:2]([C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)=[C:7]([O:8][CH3:9])[N:6]=[CH:5][N:4]=1
Reactant: OB(O)c1ccncc1
Reactant: COc1ncnc(OC)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ncnc(OC)c1-c1ccncc1
Temperature: 70 °C
Yield: 82.4 %

Procedure:
A mixture of 5-bromo-4,6-dimethoxypyrimidine (2.18 g, 10 mmol), pyridine-4-boronic acid (1.85 g, 15 mmol), K2CO3 (2.76 g, 20 mmol), and PXPd (539 mg, 1.0 mmol) in ethanol/THF (1:1, 25 mL) under argon was heated at 70° C. for 3 h. Analysis by HPLC/MS indicated that the reaction was complete. After the reaction mixture was cooled to room temperature, the solvent mixture was removed under reduced pressure. The residue was dissolved in EtOAc (30 mL) and washed with saturated aqueous NaCl (20 mL), then dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography eluted with ethyl acetate-hexanes to obtain the title compound (1.79 g) as a white solid. 1H NMR (CDCl3): δ 3.97 (s, 6H), 7.36 (d, 2H), 8.47 (s, 1H), 8.64 (d, 2H).
Reaction SMILES: CC1C=CC(S(O/[N:12]=[C:13]2\[CH2:14][CH2:15][CH2:16][C:17]3[O:21][CH:20]=[C:19]([C:22]([OH:24])=[O:23])[C:18]\2=3)(=O)=O)=CC=1.C([O-])(=[O:27])C.[K+].C(O)C>O>[O:27]=[C:13]1[NH:12][C:18]2[C:19]([C:22]([OH:24])=[O:23])=[CH:20][O:21][C:17]=2[CH2:16][CH2:15][CH2:14]1
Reactant: Cc1ccc(S(=O)(=O)O/N=C2\CCCc3occ(C(=O)O)c32)cc1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C1CCCc2occ(C(=O)O)c2N1
Yield: 35.8 %

Procedure:
A mixture of 1.0 g of (E)-4,5,6,7-tetrahydro-4-[[[(4-methylphenyl)sulfonyl]oxy]imino]-3-benzofurancarboxylic acid, 5.9 g of potassium acetate, 23 ml of ethanol and 39 ml of water is heated at reflux for 48 hours. The reaction mixture is concentrated in vacuo, 80 ml of methylene chloride added and the separated organic layer washed with water, brine and dried with Na2SO4. The organic layer is concentrated in vacuo to a solid which is purified by chromatography on a preparative silica gel plate by elution with 0.5% acetic acid in ethyl acetate. The eluted band is washed with 1% acetic acid in ethyl acetate. The organic layer is dried with Na2SO4 and concentrated in vacuo to give 200 mg of off-white solid which is crystallized from ethyl acetate-hexane to give 165 mg of the desired product as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]=[C:10]=[O:11])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[CH3:18][N:19]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([NH2:28])[C:22]=2[CH:21]=[N:20]1.N1C2C=CC=C(N)C=2C=N1>>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:8][NH:9][C:10]([NH:28][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:22]=1[CH:21]=[N:20][N:19]2[CH3:18])=[O:11]
Reactant: Cn1ncc2c(N)cccc21
Reactant: O=C=NCc1ccc(N2CCCCC2)c(F)c1
Agent: Nc1cccc2[nH]ncc12
Product: Cn1ncc2c(NC(=O)NCc3ccc(N4CCCCC4)c(F)c3)cccc21

Procedure:
The title compound was prepared using the procedure described in Example 89B using 1-[2-fluoro-4-(isocyanatomethyl)phenyl]piperidine and 1-methyl-1H-indazol-4-amine instead of 1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A. NMR (DMSO-d6) δ 9.19 (s, 1H), 8.22 (s, 1H), 7.25 (m, 4H), 7.18 (d, 2H), 4.31 (s, 2H), 4.00 (s, 3H), 3.15 (m, 4H), 1.77 (m, 4H), 1.66 (m, 2H); MS (ESI) (M+H)+ 382.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH2:15][Cl:16])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.[C:27](=[O:30])([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:16].[ClH:16].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH2:15][N:21]2[CH2:26][CH2:25][N:24]([CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:30][CH3:27])[CH:6]=3)[CH2:23][CH2:22]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(-c2ccccc2CCl)cc(OC)c1OC
Reactant: C1CNCCN1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(-c2ccccc2CN2CCN(Cc3ccccc3-c3cc(OC)c(OC)c(OC)c3)CC2)cc(OC)c1OC
Product: Cl
Temperature: 80 °C
Reaction time: 4 h

Procedure:
2-(3,4,5-Trimethoxyphenyl)benzyl chloride (298 mg) and piperazine (43 mg) were dissolved in DMF (5 mL), and to the solution potassium carbonate (138 mg) was added. The mixture was stirred at 80° C. for 4 hours and concentrated under reduced pressure. Water was added to the residue to conduct extraction with chloroform. The resultant organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=40:1) to obtain a free base of the title compound. This compound was dissolved in ethyl acetate, and to the solution an ethyl acetate solution of 4 M hydrogen chloride was added to provide a dihydrochloride.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([OH:12])=O)[C:2]1=2.C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C)C=O>[O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([Cl:16])=[O:12])[C:2]1=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc2c1OCC2
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc2c1OCC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.9 %

Procedure:
2,3-Dihydrobenzo[b]furan-7-oic acid (3 g) (see Preparation 32) was suspended in anhydrous dichloromethane (30 ml) and oxalyl chloride (3.5 g) added, followed by addition of dimethylformamide (3 drops). The mixture was stirred at room temperature for 2.5 hours, the solvent then removed under reduced pressure, the resulting residue dissolved in dichloromethane and the solvent removed under reduced pressure. The residue was again dissolved in dichloromethane and the solvent removed under reduced pressure to give 2,3-dihydrobenzo[b]furan-7-oyl chloride as a pink solid (3.3 g).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([CH:14]=O)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[Br-].[CH2:19]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:20]1(/[CH:19]=[CH:14]/[C:12]2[NH:11][N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=3)[CH:13]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1cc(-c2ccc(C(F)(F)F)cc2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cc(/C=C/c3ccccc3)[nH]n2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 40.1 %

Procedure:
3-[4-(Trifluoromethyl)phenyl]-1H-pyrazole-5-carbaldehyde (1.20 g, 5.00 mmol) was dissolved in N,N-dimethylformamide (10 mL), benzyltriphenylphosphonium bromide (3.25 g, 7.50 mmol) and potassium carbonate (2.76 g, 20.0 mmol) were added, and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1-1:2) to give the title compound (630 mg, yield 40%) as colorless crystals. MS: m/z 315 (MH+), 1H NMR (CDCl3) δ: 6.79 (1H, s), 6.99 (1H, d, J=16.5 Hz), 7.10 (1H, d, J=16.5 Hz), 7.28-7.39 (3H, m), 7.41-7.47 (2H, m), 7.64 (2H, d, J=8.5 Hz), 7.87 (2H, d, J=8.0 Hz), 10.90 (1H, s).
Reaction SMILES: [N:1]#[C:2]Br.C(=O)([O-])[O-].[K+].[K+].[C:10]1([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([N:25]3[CH2:30][CH2:29][N:28](C)[CH2:27][CH2:26]3)=[N:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>CS(C)=O>[C:10]1([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([N:25]3[CH2:30][CH2:29][N:28]([C:2]#[N:1])[CH2:27][CH2:26]3)=[N:17]2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N#CBr
Reactant: CN1CCN(c2nn(-c3ccccc3)c3ccccc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CN1CCN(c2nn(-c3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.2 %

Procedure:
To a stirred mixture of 1.5 g of cyanogen bromide 2.0 g of potassium carbonate and 30 ml of dimethylsulfoxide was added, dropwise, a solution of 2.8 g of 1-phenyl-3-(4-methyl-1-piperazinyl)-1H-indazole in 30 ml of dimethylsulfoxide. The reaction mixture was stirred at ambient temperature for 1.5 hours and then poured into water. The aqueous mixture was extracted with ethyl acetate, and the extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by flash chromatography on silica gel, utilizing ethyl acetate-hexane (1:1) as the eluent, followed by recrystallization from isopropyl alcohol-water to yield 2.3 g (59%) of 4-(1-phenyl-1H-indazol-3-yl)-1-piperazine carbonitrile, m.p. 118°-120°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([C:14](=O)[CH2:15][O:16][CH3:17])[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.Cl.[NH2:21][NH2:22].C(=O)(O)[O-].[Na+].[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[OH:37])[CH:32]=O.FC(F)(F)C(O)=O>C(O)C.CO>[ClH:28].[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[C:11]3[C:14]([CH2:15][O:16][CH3:17])=[N:22][NH:21][C:12]=3[N:13]=[C:32]([C:31]3[CH:34]=[CH:35][C:36]([OH:37])=[C:29]([Cl:28])[CH:30]=3)[C:6]=2[CH:7]=1
Reactant: COCC(=O)C(C#N)c1ccc(OC)c(OC)c1
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: NN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COCc1n[nH]c2nc(-c3ccc(O)c(Cl)c3)c3cc(OC)c(OC)cc3c12
Temperature: 70 °C
Yield: 38.3 %

Procedure:
To a solution of 2-[3,4-bis(methyloxy)phenyl]-4-(methyloxy)-3-oxobutanenitrile (200 mg, 0.8 mmol) in ethanol (5 mL) was added hydrazine dihydrochloride (101 mg, 0.9 mmol). The resulting mixture was heated at reflux for 1 hour. It was cooled, pour into a saturated sodium bicarbonate solution (10 mL), and the mixture was extracted with ethyl acetate (3×10 mL). The combined extract was washed with water and brine (30 mL each), dried over sodium sulfate, filtered and concentrated to give oily residue. To this residue was added of 3-chloro-4-hydroxybenzaldehyde (189 mg, 1.2 mmol) and trifluoroacetic acid (3 mL), and the resulting mixture was heated at 70° C. for 18 hours. Then the reaction mixture was concentrated, dissolved in 10 mL of N,N-dimethylformamide and purified by preparatory reverse phase HPLC (Shimadzu LC-8A HPLC, Waters Xterra C18 30 mm×100 mm column, acetonitrile-water-trifluoroacetic buffer). After lyophillization of the pure fractions a yellow powder was obtained. The solid was dissolved in 4 mL of 1:1 methanol: 4N hydrogen chloride in dioxane, and evaporated to dryness (repeated three times) to give 4-{7,8-bis(methyloxy)-1-[(methyloxy)methyl]-3H-pyrazolo[3,4-c]isoquinolin-5-yl}-2-chlorophenol hydrochloride salt (101 mg, 0.23 mmol, 29% yield). 1H NMR (400 MHz, d6-DMSO): 10.64 (b, 1H), 7.82 (s, 1H), 7.71 (s, 1H), 7.58-7.56 (d, 1H), 7.45 (s, 1H), 7.17-7.15 (d, 1H), 4.92 (s, 2H), 4.02 (s, 3H), 3.78 (s, 3H); MS (EI) for C20H18ClN3O4: 400 (MH+).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][CH3:14])[C:10](=[O:15])[C:9]([F:17])([F:16])[CH2:8][N:7]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:6]=2[N:23]=1.[NH2:24][C:25]1[CH:40]=[CH:39][C:28]([C:29]([NH:31][CH:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[O:30])=[CH:27][CH:26]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH:18]1([N:7]2[CH2:8][C:9]([F:17])([F:16])[C:10](=[O:15])[N:11]([CH2:12][CH2:13][CH3:14])[C:5]3[CH:4]=[N:3][C:2]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([C:29]([NH:31][CH:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)=[O:30])=[CH:39][CH:40]=4)=[N:23][C:6]2=3)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CN1CCC(NC(=O)c2ccc(N)cc2)CC1
Reactant: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3)ncc21
Yield: 62.8 %

Procedure:
A mixture of 0.05 g (0.15 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-propyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-144), 0.05 g (0.17 mmole) of 4-amino-N-(1-methyl-piperidin-4-yl)-benzamide, 0.04 g (0.22 mmole) of p-toluenesulfonic acid monohydrate and 4.0 mL of 2-propanol was heated at 160 degrees for 2 hours in a microwave reactor. The cooled mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phases were extracted with dichloromethane, and the combined organic layers washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol-dichloromethane (gradient, 0:100-25:75), to give 0.051 g of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-5-propyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-benzamide (I-147).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][OH:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=1>>[Cl:38][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=1)[CH2:31][O:29][CH2:28][CH2:27][C:22]1[C:23]([CH3:26])=[N:24][O:25][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([C:6]3([C:4]([OH:3])=[O:5])[CH2:7][CH2:8]3)=[CH:10][CH:11]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCO)cc3)cc2)CC1
Reactant: Clc1cccc(CBr)c1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CCOCc1cccc(Cl)c1

Procedure:
Prepared according to the procedure described in Example 34, Step 4, using 1-{4′-[4-(2-Hydroxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 1-bromomethyl-3-chloro-benzene.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([C:10]2[O:14][C:13]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[C:17]([CH3:28])[CH:16]=3)=[N:12][N:11]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[OH:24][CH:21]([CH2:20][O:19][C:18]1[C:25]([CH3:27])=[CH:26][C:15]([C:13]2[O:14][C:10]([C:8]3[S:9][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=3)=[N:11][N:12]=2)=[CH:16][C:17]=1[CH3:28])[CH2:22][O:23][S:39]([CH3:38])(=[O:41])=[O:40]
Reactant: Cc1cc(-c2nnc(-c3ccc(CC(C)C)s3)o2)cc(C)c1OCC(O)CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2nnc(-c3ccc(CC(C)C)s3)o2)cc(C)c1OCC(O)COS(C)(=O)=O
Reaction time: 1 h
Yield: 29.3 %

Procedure:
To a solution of 3-{4-[5-(5-isobutyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol (627 mg, 1.56 mmol) and DIPEA (311 mg, 2.41 mmol) in DCM (10 mL), methanesulfonyl chloride (207 mg, 1.81 mmol) is added. The mixture is stirred at rt before another portion of DIPEA (40 mg, 0.31 mmol) and methanesulfonyl chloride (36 mg, 0.31 mmol) is added. Stirring is continued for 1 h before the reaction is quenched by adding water. The mixture is extracted with DCM. The org. extract is washed with water, dried over MgSO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 7:3 to give methanesulfonic acid 2-hydroxy-3-{4-[5-(5-isobutyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl-phenoxy}-propyl ester (220 mg) as a colourless oil; LC-MS: tR=1.08 min, [M+1]+=481.09.
Reaction SMILES: [CH2:1]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=CC=1)[CH2:2][CH2:3]CCCCCCCCC.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.C([N:27](CC)CC)C.C(Cl)(=O)C=C>C1COCC1>[CH2:13]1[CH2:1][CH2:2][CH2:3][N:17]([CH2:24][CH2:23][N:22]=[C:21]([NH2:27])[NH2:20])[CH2:16][CH2:18][CH2:19]1
Reactant: CCCCCCCCCCCCc1ccc(N)cc1
Reactant: c1c[nH]cn1
Reactant: CCN(CC)CC
Agent: C=CC(=O)Cl
Solvent: C1CCOC1
Product: NC(N)=NCCN1CCCCCCC1
Reaction time: 6 h
Yield: 95 %

Procedure:
First, 12 g (0.046 mol) of paradodecyl aniline was dissolved in 100 mL of THF and then put into a 100 mL three-neck round bottom flask. To this solution was added dropwise through a funnel over 10 minutes an acid remover prepared by mixing imidazole and triethyl amine at an equivalent mole ratio (0.023 mol). Then, to the resulting solution was slowly added dropwise through a dropping funnel over 20 minutes under a nitrogen atmosphere a solution prepared by dissolving 3.8 ml (0.047 mol) of acryloyl chloride in 20 mL of THF. At this time, the reaction mixture cooled with ice so as to keep its temperature below 5° C. Thereafter, the reaction proceeded at 0° C. for 6 hours, and then at 25° C. for 9 hours. After the completion of the reaction, the resulting solution was filtered with a filtering paper to remove salt precipitates, and then the solvent was eliminated by using an evaporator. The obtained solids were dissolved in 100 mL of dichloromethane and put into a separating funnel together with 50 mL of an aqueous solution of 10% NaHCO3 and shaken strongly to separate the aqueous solution layer and to remove the unreacted portion of acryloyl chloride. To the dichloromethane solution being separated was added 1.0 g of magnesium sulfate and the resulting mixture was stirred for 5 hours and filtered to remove a trace amount of water being dissolved in the solvent. The resulting dichloromethane solution was evaporated and then 100 mL of n-hexane was added thereto and stirred for 2 hours, and then was filtered to remove the unreacted portion of paradodecyl aniline remained in the solution. The solvent was removed from the resulting solution by using an evaporator to provide white solids of DOPAM (Yield: 95%). The chemical structure of DOPAM as synthesized was confirmed by a 1H nuclear magnetic resonance (1H-NMR) spectrum, and the results are the same as follows:
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4]1.[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1COCC1>[CH2:18]([O:1][CH2:2][C@H:3]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](CO)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](COCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 74.8 %

Procedure:
To a solution of 1.4 g (6.7 mmol) of tert-butyl [(1R,3S)-3-(hydroxymethyl)cyclopentyl]carbamate in 20 mL of anhydrous THF are added portionwise under argon, at room temperature, 0.27 g (6.7 mmol) of sodium hydride at 60% in oil. After stirring for 45 minutes, the medium is cooled to 0° C. and 0.8 mL (6.7 mmol) of benzyl bromide is added. After stirring for 1 hour at room temperature, the medium is hydrolysed with 30 mL of water and extracted with 2×100 mL of EtOAc, dried over Na2SO4, concentrated under reduced pressure and then purified by chromatography on a column of silica gel, eluting with a 99/1 DCM/MeOH mixture. 1.53 g of tert-butyl {(1R,3S)-3-[(benzyloxy)methyl]cyclopentyl}carbamate are obtained in the form of an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19]S(C)(=O)=O)[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[N:11][C:10]([CH3:13])=[N:9]1.[N-:25]=[N+:26]=[N-:27].[Na+].O>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][CH:17]([CH2:19][N:25]=[N+:26]=[N-:27])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[N:11][C:10]([CH3:13])=[N:9]1
Reactant: Cc1ncn(-c2ccc(N3C[C@H](CS(C)(=O)=O)OC3=O)cc2F)n1
Reactant: [N-]=[N+]=[N-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncn(-c2ccc(N3CC(CN=[N+]=[N-])OC3=O)cc2F)n1
Yield: 79.3 %

Procedure:
(5R)-3-[3-Fluoro-4-(3-methyl-1,2,4-triazol-1-yl)phenyl]-5-[(methanesulfonyl)methyl]-oxazolidin-2-one (Intermediate 24a) (5.432 g, 14.7 mmol), sodium azide (1.092 g, 16.6 mmol), and 18-crown-6 (0.069 g, 0.26 mmol) in dimethylformamide (15 mL) were heated to 90° C. for 3.75 hours. The reaction mixture was poured into water (200 ml) and extracted with dichloromethane (3×100 ml). The combined organic layers were washed once with brine, dried over MgSO4 and concentrated under vacuum. Chromatography on silica gel with 5% methanol in dichloromethane gave the title compound (3.7 g) as a colourless solid.
Reaction SMILES: Br[C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:16]1[S:17][CH:18]=[C:19]2[O:24][CH2:23][CH2:22][O:21][C:20]=12)CCC>CN(C=O)C>[CH2:22]1[CH2:23][O:24][C:19]2[C:20](=[C:16]([C:2]3[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=3)[S:17][CH:18]=2)[O:21]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1scc2c1OCCO2
Reactant: O=Cc1cc(Br)ccc1O
Solvent: CN(C)C=O
Product: O=Cc1cc(-c2scc3c2OCCO3)ccc1O
Temperature: 80 °C
Yield: 27 %

Procedure:
The synthesis of this compound is depicted schematically in FIG. 13. A 50 mL schlenk flask was charged with 5-bromosalicylaldehyde (2.408 g, 11.98 mmol) and Cl2Pd(PPh3)2 (0.420 g, 0.599 mmol, 0.05 equiv). To this was added 2-tributylstannyl-3,4-ethylenedioxythiophene (8.784 g, 20.37 mmol, 1.7 equiv) in 25 mL of DMF. The reaction mixture was heated to 80° C. for 18 h, over which time the reaction color changed from light yellow to dark red. The solvent was removed under vacuum and the resulting oil was dissolved in 350 mL of EtOAc and washed with dil. NH4Cl (6×100 mL). The organic layer was filtered through a pad of silica and the solvent was removed to yield a thermally- and light-sensitive yellow-green solid (0.846 g, 3.23 mmol, 27%), mp 132° C., dec. 1H NMR (CDCl3) δ10.98 (s, 1H), 9.94 (s, 1H) 7.92 (d, 1H, J=2.3 Hz), 7.84 (dd, 1H, J=2.4 and 8.7 Hz), 7.00 (d, 1H, J=8.7 Hz), 6.29 (s, 1H), 4.34-4.25 (m, 4H). MS m/z 262 (M+). HRMS (FAB) found m/z 263.0378 (M+H+); calcd for C13H11O4S m/z 263.0378 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C@@H:15]([NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:26]=3[CH2:33][CH3:34])[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:13][CH:14]=2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.N[C@H](C1NC=C(C2C=CC(C(N)=O)=CC=2)N=1)CC1C=CC=CC=1>C1COCC1>[NH2:32][CH2:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]([NH:23][C@H:15]([C:12]2[NH:13][CH:14]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([C:1](=[O:3])[NH2:2])=[CH:9][CH:8]=3)[N:11]=2)[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:35])=[C:26]([CH2:33][CH3:34])[CH:27]=1
Reactant: CCc1cc(C#N)ccc1C(=O)N[C@@H](Cc1ccccc1)c1nc(-c2ccc(C(N)=O)cc2)c[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC(=O)c1ccc(-c2c[nH]c([C@@H](N)Cc3ccccc3)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1cc(CN)ccc1C(=O)N[C@@H](Cc1ccccc1)c1nc(-c2ccc(C(N)=O)cc2)c[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Part E: N-{(S)-1-[4-(4-Carbamoyl-phenyl)-1H-imidazol-2-yl]-2-phenyl-ethyl}-4-cyano-2-ethyl-benzamide: The product from Example 143 Part D (90 mg, 0.51 mmol), Bop reagent (265 mg, 0.61 mmol), and triethylamine (0.42 mL, 1.5 mmol) were added together with 5 mL of THF. The mixture was stirred at RT under N2 for 15 minutes and (S)-4-(2-(1-amino-2-phenylethyl)-1H-imidazol-4-yl)benzamide prepared using the methods described in Examples 2 and 28 (365 mg, 0.51 mg) was added. The resulting mixture was heated at 75° C. for 70 minutes. The THF was removed, and the residue was dissolved in EtOAc. It was washed with waster and brine, dried over MgSO4, concentrated, and purified by flash chromatography (silica, EtOAc/hexane) to give 80 mg of the desired product. MS: 464.4 (M+1)+.